title: EGFR trans-activation by urotensin II receptor is mediated by β-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy.
abstract: Urotensin II (UTII) and its seven trans-membrane receptor (UTR) are up-regulated in the heart under pathological conditions. Previous in vitro studies have shown that UTII trans-activates the epidermal growth factor receptor (EGFR), however, the role of such novel signalling pathway stimulated by UTII is currently unknown. In this study, we hypothesized that EGFR trans-activation by UTII might exert a protective effect in the overloaded heart. To test this hypothesis, we induced cardiac hypertrophy by transverse aortic constriction (TAC) in wild-type mice, and tested the effects of the UTII antagonist Urantide (UR) on cardiac function, structure, and EGFR trans-activation. After 7 days of pressure overload, UR treatment induced a rapid and significant impairment of cardiac function compared to vehicle. In UR-treated TAC mice, cardiac dysfunction was associated with reduced phosphorylation levels of the EGFR and extracellular-regulated kinase (ERK), increased apoptotic cell death and fibrosis. In vitro UTR stimulation induced membrane translocation of β-arrestin 1/2, EGFR phosphorylation/internalization, and ERK activation in HEK293 cells. Furthermore, UTII administration lowered apoptotic cell death induced by serum deprivation, as shown by reduced TUNEL/Annexin V staining and caspase 3 activation. Interestingly, UTII-mediated EGFR trans-activation could be prevented by UR treatment or knockdown of β-arrestin 1/2. Our data show, for the first time in vivo, a new UTR signalling pathway which is mediated by EGFR trans-activation, dependent by β-arrestin 1/2, promoting cell survival and cardioprotection.
authors.affiliation: Division of Cardiology, Federico II University of Naples, Via Pansini 5, Naples, Italy. espogiov@unina.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Cinzia
authors.initials: C
authors.lastname: Perrino
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.forename: Gabriele G
authors.initials: GG
authors.lastname: Schiattarella
authors.forename: Francesco
authors.initials: F
authors.lastname: Borgia
authors.forename: Anna
authors.initials: A
authors.lastname: Sannino
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Pironti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Serafino
authors.forename: Anna
authors.initials: A
authors.lastname: Franzone
authors.forename: Laura
authors.initials: L
authors.lastname: Scudiero
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Ciro
authors.initials: C
authors.lastname: Indolfi
authors.forename: Massimo
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019390:Arrestins / Q000502:physiology*; D001794:Blood Pressure; D006332:Cardiomegaly / Q000503:physiopathology*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015533:Transcriptional Activation; D014579:Urotensins / Q000502:physiology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C512325:urotensin II receptor, mouse; D004815:Epidermal Growth Factor; C029677:urotensin II; D066246:ErbB Receptors